This research expands on new and novel findings from this group that show definitively that cadherin complexes, essential cell-cell adhesion proteins in all cohesive tissues, are tension sensors that probe the mechanical environment of the cell to regulate a wide range of critical functions including morphogenesis, wound healing, tissue organization, and metastasis. Increasing evidence shows that crucial biological functions, in development and in adult tissues, are regulated by the mechanical environment, which couples to the cytoskeletal network and nucleus via cell surface adhesion proteins. Although integrins are well-established force sensors, our new findings show that cadherins are also critical mechanical and signaling hubs in tissues. In this program, we advance our initial investigations to elucidate the force-actuated, molecular cascades in the cadherin-specific mechanotransduction pathway. Our innovative combination of mechanical measurements and dynamic fluorescence imaging has substantial advantages over competing technologies because it enables the application of direct, controlled localized force to cadherin adhesions, while simultaneously imaging the rapid, early molecular events in mechanotransduction, in a high throughput format. By enhancing this methodology with powerful biochemical tools and complementary studies of the impact of endogenous contractile force on cell-cell junctions, we are strategically positioned to address fundamental, unresolved questions regarding mechanisms of force propagation through tissues. This proposed program will significantly advance our understanding of mechano-transduction in tissues, and pave the way towards our long-term goals of developing targeted therapies for metastasis or leaky blood vessels, and of enhancing tissue regeneration and wound healing. PUBLIC HEALTH RELEVANCE: This proposed program expands on new findings from this group showing that cadherin complexes, which are crucial intercellular adhesion proteins in all cohesive tissues, sense mechanical force to regulate molecular and signaling cascades governing such functions as wound healing, morphogenesis, tissue regeneration, and metastasis. These studies will make major advances in the understanding of mechanisms by which force regulates cadherin-dependent functions, in the broader context of mechano-biology, and pave the way towards our long-term health related goals of developing targeted therapies for metastasis, leaky blood vessels, wound healing, and tissue regeneration.